ClinVar Genomic variation as it relates to human health

Variant summary: ATM c.5821G>C (p.Val1941Leu) results in a conservative amino acid change located in the PIK-related kinase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251056 control chromosomes, predominantly at a frequency of 0.00026 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing breast/ATM-related cancer and/or Ataxia Telangiectasia. However, the variant was also reported in 10 / 9884 women (i.e. with a frequency of about 0.001), who were older than 70 years of age, and never had cancer (FLOSSIES database), which might suggest a benign outcome for the variant. c.5821G>C has been reported in the literature in individuals affected with breast cancer (e.g. Shayeghi_1998, Renwick_2006, Maxwell_2015, Pereira_2022), other tumor phenotypes such as chronic lymphocytic leukemia (CLL), Lynch syndrome-associated cancer and/or polyps, pediatric low grade glioma (e.g. Skowronska_2011, Yurgelun_2015, Zhang_2015, Tung_2015) and also in several healthy controls (e.g. Tavtigian_2009, Skowronska_2011, Tiao_2017, Yu_2022). Recent case-control studies showed that the frequencies of this variant are similar in cases (breast cancer, prostate cancer, or pancreatic cancer) and controls, indicating this variant does not associate with breast, prostate, or pancreatic cancer (Dorling_2021, Karlsson_2021, Yu_2022). Furthermore, a co-occurrence with another pathogenic variant (BRCA1 c.3607C>T, p.Arg1203X) has been observed for this variant (internal sample). Using an ATM-null lymphoblastoid cell line (LCL) transfected with the variant of interest, Barone et al demonstrated an approximately 50% decrease in protein expression (or stability), yet no significant decrease in specific kinase activity (Barone_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 33471991, 33436325, 25503501, 35980532, 16832357, 9764584, 21933854, 19781682, 28652578, 25186627, 29909963, 35047863, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 127412). Based on the evidence outlined above, the variant was classified as likely benign.

Converted during submission to Uncertain significance.

The ATM c.5821G>C (p.Val1941Leu) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. A functional study has shown reduced ATM protein level and kinase activity (PMID: 19431188). This variant has been identified in individuals with breast cancer (PMID: 16832357, 25186627, 28779002, 29522266, 35980532), an individual undergoing clinical genetic testing for Lynch syndrome (PMID: 25980754), and an individual with multiple primary tumors or with a single primary tumor and a first-degree relative with multiple primary tumors (PMID: 29909963). In addition, in case-control studies the variant was present at similar or low frequencies in breast cancer patients compared to control subjects (PMID: 19781682, 28779002). This variant is present 10x in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16014569, 19781682, 21787400, 16832357, 21933854, 25503501, 25980754, 26580448, 25925381, 28971906, 29909963, 29522266, 25186627, 28779002, 28652578, 31843900, 9764584, 33471991, 33436325, 19431188, 35980532, 35534704, 34326862, 34262154)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The p.V1941L variant (also known as c.5821G>C), located in coding exon 38 of the ATM gene, results from a G to C substitution at nucleotide position 5821. The valine at codon 1941 is replaced by leucine, an amino acid with highly similar properties. One functional analysis of this variant showed an associated reduction, but not absence, of ATM kinase activity (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). Across numerous studies, this alteration has been observed in multiple cancer cohorts and control groups (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Skowronska A et al. Haematologica. 2012 Jan;97:142-6; Tung N et al. Cancer. 2015 Jan;121:25-33; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Decker B et al. J Med Genet. 2017 11;54:732-741; Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

ATM: PS3:Supporting

The ATM c.5821G>C variant is predicted to result in the amino acid substitution p.Val1941Leu. This variant has been identified in individuals with breast cancer (Table S2, Renwick et al. 2006. PubMed ID: 16832357; Table S1, Maxwell et al. 2015. PubMed ID: 25503501, Table S4, Bhai et al. 2021. PubMed ID: 34326862), chronic lymphocytic leukemia (Table S2, Skowronska et al. 2012. PubMed ID: 21933854), and suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). Functional analysis showed that this variant results in reduced ATM protein activity (Barone et al. 2009. PubMed ID: 19431188). However, in case-control studies, this variant was identified with similar frequencies between controls and individuals with breast cancer or chronic lymphocytic leukemia (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table S2, Skowronska et al. 2012. PubMed ID: 21933854). This variant is reported in 0.025%of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/127412). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.